Our previous studies suggest that reductive stress (a decrease in free cytosolic NAD+/NADH is an early metabolic imbalance contributing to energy deficiency in sciatic nerve in both STZ-diabetic (D) and galactose -fed (G) rats. Others attribute the diabetes-induced energy deficiency and decreased MNCV to hypoxia (caused by decreased blood flow) rather than to metabolic factors. The present study was designed to: 1) evaluate the mitochondrial redox state of NAD-couples and parameters of energy metabolism in sciatic nerve in rats with short-term (10 d) STZ-diabetes and galactosemia, and 2) assess the contribution of hypoxia to deficiency in both models. Experiments were performed on male STZ-diabetic (D) and 50% galactose-fed (G) rats treated with/without the aldose reductase inhibitor, tolrestat, at a dose of 100 mg/kg bwt/day in the diet. The levels of B-hydroxybutyrate (B-HB), acetoacetate (AA), GA3P 3-PG, pyruvate, lactate, ATP, ADP, phosphocreatine (PC) and creatine (C) were assayed in individual nerves spectrofluorometrically by enzymatic methods; polyols and myoinositol were quantified by GCMS. Free mitochondrial NAD+/NADH ratios (cristae) were calculated from the B-HB dehydrogenase system while free cytosolic ATP/ADP*Pi -from the GA3P dehydrogenase 3-PG kinase system. Data are presented as Mean + SD, Polyol levels increased to 1.75 +0.35 in D (vs 0.120+0.021 umol/g in C), and 19.7+2.1 in G (galactitol was not detected in C) while myo-inositol levels decreased in both models. ATP levels and ATP/ADP decreased in D (to 0.551 + 0.088 and 1.01 + 0.18, vs 0.696 + 0.193 umol/g and 1.53 + 0.45 in C), and unchanged in G. PC levels and PC/C ration decreased in G (to 1.20 + 0.26 and 0.35 + 0.13 vs 1.70 + 0.29 umol/g and 0.61 +0.20 in C), and unchanged in D. Free cytosolic ATP/ADP*Pi decreased in both models. Mitochondrial NAD+/NADH (which has been reported to be decreased in ischemic and happiest tissues), was not different from C in both D and G (29.8 + 10.7 and 27.1 + 10.1 vs 30.7 + 11.7 in C)> ARI deceased polyols to 0.014 + to 0.007 in D and 1.17 + 0.3 in G, and increased myo-inositol, PC levels, PC/C and free cytosolic ATP/ADP*Pi rations in both D and G. ATP levels and ATP/ADP ratios were increased by ARI in G but not in D, while mitochondrial NAD+/NADH was not affected in either D or G. In conclusion, nerve energy metabolism is impaired at early stages in both models. The absence of mitochondrial redox changes in short-term D and G treated with/without ARI implies that 1) hypoxia (even if present) is insufficient to decrease NADH oxidation by respiratory chain, and, therefore, does not contribute to energy deficiency, and 2) preventive effects of ARIs on nerve energy metabolism in short-term D and G are not mediated via an increase in oxygen supply.